It is well established that there are individual differences in taste intensity perception resulting from genetic variation in taste receptors or other peripheral taste physiology [1-8]. Much less explored is the possibility for other sources of variability. Guided by new evidence from the prior project period which indicates that the gustatory system is an integrated oral sensory system that exhibits both transient and long-term plasticity, the proposed work will combine psychophysics and neuroimaging methods in humans to investigate central as well as peripheral neural mechanisms that influence taste sensitivity. In aim 1 we will test the hypothesis that a central gain mechanism plays a significant role in individual differences in taste perception in humans. Whereas peripheral explanations of variance in sensitivity are often specific to a particular quality or chemical, we propose to develop and validate a neurobiological model of brain circuitry that determines overall taste system sensitivity. In aim 2 we will investigate whether prolonged directed attention to oral but not extra-oral sensations increases taste and flavor sensitivity via modulation of the anterior insula or the proposed central gain mechanism. In the first period of this project we identified a higher-order cortical network that modulates processing in gustatory cortex in the service of goal directed behaviors [9-12]. New pilot data suggests that engaging in a psychophysical task that demands prolonged attention may modulate this mechanism. We will test this hypothesis by comparing changes in taste intensity and the blood oxygen level dependent (BOLD) responses in gustatory circuits before and after tasks requiring directed attention to flavors vs. visual stimuli. In aim 3 we investigate the possibility of a dietary influence on gustatory sensitivity. Significant controversy surrounds the possibility that consumption of artificial sweeteners (AFS) leads to weight gain. Some studies have found correlations between AFS use and weight gain and/or diabetes [13-16] while others have indicated that AFSs may aid in weight loss [17] or have no effects on body mass index (BMI) [18]. Given that the five FDA approved AFSs are found in thousands of foods [19] this marks a clear and significant gap in knowledge. Our preliminary data demonstrate a 3-fold decrease in sweet taste sensitivity following consumption of a beverage sweetened with two packets of Splenda for just 10 days. These data provide strong evidence that repeated exposure to sucralose reduces perception of sweet taste intensity, most likely by down regulation of the sweet taste receptor. Overall, identifying central mechanisms of taste modulation related to gain modulation and directed attention, as well as a possible peripheral mechanism triggered by consumption of an AFS, the proposed work will advance understanding of sources of individual differences in taste that are relevant to food choice and consumption.